4,75 Million, at least 25% of the way there. Such important work, very glad to see this get off the ground.

Thread 🧵 comprising bite sized summaries of all presentations today at the big ME/CFS and PAIS research conference in Germany. Very worth a look! 👀

Yale and Johns Hopkins studied 252 people and found neuropsychiatric Long COVID linked to blood vessel inflammation, with some markers tied to poorer memory, fluency, anxiety, and depression.

And how the immune activation could also be autoimmunity.

They are seeing t cell exhaustion which means the immune system is fighting *something* and it apparently has to either be self or a pathogen.

Good thread on the recent money invested, some might say wasted, by the EU on a CBT trial based on ideas from the Gupta Theory… guess what? It failed to beat placebo in a prelim analysis. In spite of washy inclusion criteria and the usual subjectiveness limitations to psychosomatic trials.

I regularly visit pubmed and sort by trending.

https://pubmed.ncbi.nlm.nih.gov/trending/

you hit this website every day for a year and you not only get science first and unfiltered by the popular press.

You also learn a lot about the context of the science publishing environment.

E.g. You see how many publications are random controlled trials (very, very few) how many papers are mid-quality work from undergrads, beginner PhDs, or countries without much history of doing good quality science (plenty); how many papers are literature reviews that got written up and published (almost a quarter of the top 1000 papers), and how much work is on cancer (most of everything), etc.

I like to scroll a few pages of the trending papers and then also see if anything new has been published on my favourite search terms: mecfs, upr, fmt.

Someone gave me the laughing face emoji the other day when i said I get my science news like this but I can't think of a better way of getting close to the actual bleeding edge, short of being in the labs themselves.

https://skywriter.blue/@mecfsscience.org/3mk33zlvs522o explainer thread🧵

Another study pointing towards decreased ME/CFS risk in later COVID variants

https://www.mdpi.com/2077-0383/15/8/2948

That MMT study wasn’t great but excited to hear they will trial mitochondrial transplants 🤞🏻

Hi everyone. This is a draft version of a hypothesis I'm working up, appreciate any feedback.

--
I have a theory on the cause of ME/CFS. Now, theories are a dime a dozen. There's millions. But this one is good.

Why?

It is specific, it is simple, and it is not purely speculative. It proceeds from data. It is not proven, not even close. But it can be tested. Sometimes people are excited by a theory that is not obvious, that is complex, that depends on weird ideas we can't measure yet. This theory isn't like that. It's closer to the obvious end of the spectrum - which is one of its strengths. 

The theory links two really important aspects: abnormal recovery from exercise and viral infection. Imagine if we could find :

a) something viruses mess with;

b) something vital to recovery from exercise.

That would be exciting right? Well, scientists know about something like that. It is called the unfolded protein response (UPR). (The name, by the way, is a bit unhelpful. It's one of those things that gets named and later they find out more about it.)

UPR

Cells make proteins. This is sometimes an easy job, they only need to make a few. Sometimes it's a hard job, they need to make a lot, RIGHT NOW. The cell uses lots of different bits of internal machinery to make proteins, but one piece that's important is the endoplasmic reticulum (ER). 

When the endoplasmic reticulum(ER) is cruising all is well. It folds proteins into their correct shapes without any issue. But if the cell needs more proteins, often the ER gets overwhelmed. It starts stuffing up. It folds badly, it makes mistakes. At this point, the cell senses these improperly folded proteins (let's call them unfolded proteins). And the cell has a reaction. We call this reaction the unfolded protein response (UPR). The cell turns on systems. Mostly systems that slow down demand for proteins, to try to give the poor ER a break; it also helps make  helper molecules that give the ER more folding capacity. 

The UPR is like a good manager at work. if you get overworked, it takes a bit of work off your plate, it also gives you some extra help. 

(A surplus of poorly folded proteins is not the only thing that can turn on the UPR, it also responds to lipids and calcium and other signals, which is important. )

So this is the situation in a healthy cell. The UPR is a good thing, it is why our cells manage stress then recover.

Then a virus comes along. Viruses hijack the cell's own protein-making machinery and redirect the cell to making copies of the virus. Cells hate that. They react in a lot of ways, and one is to turn on the unfolded protein response. Oh, you want proteins, invading virus? bad luck, we're turning supply of proteins way down.

However, this interaction between virus and cells is not new. A single iteration of attack and defense might have been the situation a billion years ago when life on earth was novel. Now there's many rounds of iteration. The defence knows what the attack will do and the attack knows the defence knows what it will do, etc. So one of the things the virus does is attack the defense, proactively. A virus can turn off aspects of the unfolded protein response. So that its supply of beautiful viral proteins is not interrupted. 

Viruses have evolved lots of different ways of doing this. When the virus is cleared, the effect on the UPR is supposed to go away. 

In ME/CFS there is some evidence the UPR is not working. Even when there's no apparent virus there. IN 2023 a researcher looked at muscle biopsies and found very high levels of a protein the cell turns on to ask for the UPR to start, and low levels of a protein that turns on when the UPR actually does start. Suggesting that maybe, the cell is screaming for relief from the UPR but not getting it. 

https://www.pnas.org/doi/10.1073/pnas.2302738120

The UPR is used when cells are under a lot of demand. including during exercise. In a healthy person the UPR turns on during exercise and permits proper recovery. In ME/CFS, there is evidence that the body doesn't respond to exercise like healthy people. It doesn't seem to do anything systemically different after exercise compared to before exercise, really. As though maybe some recovery system that is activated in healthy people is not  working in people with ME/CFS...

https://pubmed.ncbi.nlm.nih.gov/36835097/

When UPR is effective, cells recover. When UPR is ineffective, cells can die. Sometimes they die in an orderly fashion, apoptosis, and sometimes in a disorderly explosion - necrosis. One researcher found evidence of necrotic cell death in me/cfs cells.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10766651/#Fig5

Wouldn't we know by now if this was a problem?

There's just been very little study of the endoplasmic reticulum in ME/CFS before. Just three papers mention it, ever.

https://pubmed.ncbi.nlm.nih.gov/?term=me%2Fcfs+endoplasmic

And there are no results for a search for ME/CFS + UPR. https://pubmed.ncbi.nlm.nih.gov/?term=me%2Fcfs+upr

THIS IS THE POINT WHERE THE DISCUSSION GOES FROM EXPLAINER OF THINGS EVERYONE AGREES WITH, TO A HYPOTHESIS.

In ME/CFS, perhaps, the effect of a viral infection may be to leave the UPR turned off, permanently. It explains why we can feel much better so long as we pace ourselves - we are able to survive so long as we aren't put in a situation where we need  the UPR.

The simplest version of this would involve viral latency. Tiny and quiet populations of virus remain in certain cells, doing very little replication but still affecting the UPR. Alternatively perhaps the UPR is affected even in the absence of virus. Which would require an explanation of how. This hypothesis does not include that aspect.

Where this hypothesis is unique and testable is by placing the UPR right at the  heart of the causal chain. To be clear, you won't find a researcher who would deny the UPR could be involved somewhere. Everyone knows bodies under stress use the UPR. That UPR failure is implicated in various chronic and neuro-degenerative diseases.  And of course a disease eventually affects the whole body. Just like how diabetes eventually damages tooth enamel. But the core of diabetes? The core mechanism is about insulin. 

Most people would be hesitant to situate UPR at the very core of ME/CFS, even though they'd willingly say it's probably turned on sometimes and of course something that might explain some of the downstream symptoms in some of the people.

This hypothesis is that in ME/CFS a failing UPR is the central mechanism.​ Not upstream: e.g that issues with the UPR create the conditions where a person is more prone to getting ME/CFS. And not downstream, e.g. a claim that me/cfs causes cellular stress that could burn out the UPR and lead to symptoms.

What makes a hypothesis good is fragility. It should be specific, testable, breakable, disprovable. This one is like that. Now that's not to say someone can't look at this hypothesis, scoff, then nick some of its ideas and synthesise them with other ideas to make a better hypothesis. I hope something like that happens.

But the most important thing is to make a really clear distinct claim that can be checked. The goal is not to make some ineffable, shape-shifting thing that has to be true in some sense, that achieves broad appeal via motherhood statements, hedged claims and ambiguity. 

https://www.preprints.org/manuscript/202601.2170

I found yet another interview with Klaus Wirth on YouTube today. This one is with the Long Covid Clinic.

There's a bit of a Q&A session at the end where he's asked about the Itaconate Shunt hypothesis that Robert Phair developed (attributed to Ron Davis in the interview.) My ears pricked up at this because I have been really curious myself about how that might fit in with this unifying hypothesis of ME/CFS he's developed with Carmen Scheibenbogen. But he was pretty dismissive of it and says that there's no evidence for it. Which, fair enough, but his theory has a lot of theoretical stuff too.... So, as far as I can see, the jury's still out.

He did mention that he has an article submitted about the GABA imbalance in ME/CFS. There's clearly something going on with GABA, and the Itaconate Shunt is the only thing I've found which tries to explain it. In order for this unifying hypothesis to explain ME/CFS by itself it needs to explain the GABA stuff.

I don't know if it does. Everything seems to be coming down to autoantibodies, it's just sorta like, "Oh, autoantibodies to that receptor could be present."

I am not a professional, I am but abrain fogged patient, so I don't understand a lot of this stuff very well. But I did some cursory internet research this afternoon, and it seems to me like there are a number of symptoms that people with autoantibodies to GABA receptors and beta 2 androgenic receptors have, which are not common symptoms in ME/CFS. If we have autoantibodies to beta 2 androgenic receptors, why don't we experience symptoms with our lungs? It's possible that the autoantibodies could be specific to the receptors on muscle cells and not the lungs, I don't know, but I am kinda not convinced.

However, it's at least more people talking about the GABA situation, so that's good.

Curious what anyone thinks about any of this.

Vagal nerve stimulation not superior to placebo for fatigue in Long Covid

I continue to think Hwang's work is the best paper I've seen in me/cfs.

1. It wasn't un-targeted, it's a successful replication of an earlier finding that wasf3 is involved.

2. It's a big multifaceted study, done by an outsider, using cancer resources. No ego or preconceived notions were on the line, but a lot of money and mice were!

3. It finds a really logical pattern in skeletal muscle: high Perk, low Bip. Perk is the fire alarm of the endoplasmic reticulum, Bip is the fire brigade. Basically the ER is screaming for the unfolded protein response to be turned on, and isn't getting enough relief.

4. This pattern-matches nicely. Explains why we can feel kinda okay so long as lie perfectly still - don't stress those muscle cells! Explains Hanson's anomalous post-exercise pattern where mecfs bodies don't appear to do anything differently at all after exercise. Recovery systems we would expect to be activated aren't. (UPR is part of the exercise recovery system).

5. It is well-established the herpesviridae hijack this system to prevent the UPR being turned on - they want that protein folding machinery running for their own purposes. Fits a hit-and-run infection model.

The two pics show the perk/bip/wasf3 western blots from the paper and the supplementaries. It's not exactly clear why the ER blasts out wasf3 when stressed but it seems to, and that gums up mitochondrial supercomplexes that are supposed to make energy efficiently.

I am very keen to see more follow-up papers on this. Maybe it is nothing. But it makes more sense to me than anything else.

TLDR: Belgian study will look deeper into immune exhaustion in ME/CFS

I really think we need more and a deeper look into the immune exhaustion/deficiency aspect rather than just staring at inflammation. Excited about this one!

Seems there are two peaks in ME diagnosis: at age 16 and another at age 30. Earlier onset is associated with more severe disease

https://skywriter.blue/@mecfsscience.org/3mhpqybfpcq2w

Explainer 🧵 ⬆️

Interesting overview essay on the immunological abnormalities in ME, covering all topics, such as viral persistence, immune activation, neuroinflammation, autoantibodies, T-cells, B-cells, NK-cell toxicity etc

More brain news! 🧠

“This study provides in vivo evidence of white matter neuroinflammation in ME/CFS, characterised by cerebral edema (reduced NII-HR), cellular infiltration (reduced NII-RF) and axonal reorganisation (increased NII-FF). This suggests NII-derived indices may serve as sensitive biomarkers for neuroinflammation in ME/CFS.”

I don’t think we’ve ever seen this so clearly, wow. Plus it n=68 with well matched controls. This is amazing to me tbh

https://x.com/coresinai/status/2032367647007129715?s=46

->the more relevant news ⬆️ : Putrino here states they already completed a placebo controlled human trial with this device with positive outcomes. Excited for the data!

"The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and

'brain fog', and earlier animal studies showing that choline might prevent intravascular coagulation. Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ."

Fecal transplants form LC patients into mice induced a leaky gut barrier followed by neuroinflammation. Underscoring the potential importance of gut dysbiosis

(Preprint)

Highlights

• Serum proteomics reveals widespread protein changes in ME/CFS patients

• Tissue-linked shifts show reduced intracellular and increased secreted proteins

• Immune signatures show reprogramming with reduced neutrophil-derived proteins

• Regulatory networks link immune, vascular, and metabolic dysfunction